Various forms of macular degeneration may be caused or exacerbated by the accumulation of A2E, a toxic bisretinoid that arises in a non-enzymatic side-reaction of the visual cycle. A2E is resistant to degradation, and accumulates in the lysosomes of retinal pigment epithelial cells throughout the lifespan.

In age-related macular degeneration, A2E-levels are thought to reach a toxic threshold, causing lysosomal failure and degeneration of the RPE and then the photoreceptors that depend on it. In Stargardt’s disease, A2E accumulation is congenitally accelerated, resulting in early-onset macular degeneration, probably due to the same mechanism.  Approximately 10% of patients ages 66 to 74 will have findings of macular degeneration and the prevalence increases to 30% for patients ages 75 to 85.

A2E was targeted for therapeutic intervention with lysosomal degrading enzymes in 2008.  SENS researchers appealed to supporters across the world to provide soil samples in their screening for microbial enzymes which could degrade this compound.  This helped to contribute to the identification of numerous A2E degrading enzymes.  From all A2E peroxidases tested (from this and other sources), five were marked as candidate enzymes. These enzymes were modified with glycosylation patterns which would allow them to be recognized by human RPE cells and subsequently localized to the A2E-loaded lysosomes. This modification should allow for the post-translational addition of mannose (an identifying carbohydrate) which is detected by mannose receptors which induce lysosomal targeted endocytosis.

SENS researchers are now culturing human RPE cells to verify lysosomal targeting through immunocytochemistry.  Efforts are also underway to improve enzymatic activity through the creation of a chimeric enzymes.